Full text unavailable from EThOS. Please contact the current institution’s library for further details.

Abstract:

Intraocular inflammation encompasses a diverse group of diseases which account for up to
20% of severe vision loss, particularly following pathological neovascularisation in the
retina. Nowadays, the use of corticosteroids is still the main armamentarium to manage
these devastating conditions. Clearly safer, more target-specific and effective drugs are
needed. Experimental autoimmune uveoretinitis (EAU) is an animal model for human
intraocular inflammation. It is well known that myeloid derived cells substantially contribute
to the pathological activities in this model. The aims of my PhD project were: to understand
how myeloid-derived cells contribute to retinal damage in the EAU and to investigate
whether modulating these cells can control retinal inflammation and associated retinal
angiogenesis.
Firstly, we showed that the deletions of both CCL2 and CX3CR1 resulted in reduced retinal
inflammation in EAU. In the CCL2/CX3CR1 double knockout EAU mice, the macrophage
infiltration was reduced and the inflammation was dominated by neutrophils at the acute
stage. A reduction in macrophage infiltration was associated with reduced retinal
angiogenesis at the chronic stage of EAU. Secondly, we found that SOCS3 in myeloid cells
played an important role in EAU. The LysM-Cre-SOCS3f11f1 mice had an earlier onset and
more severe retinal inflammation after immunisation. LysM-Cre-SOCS3f11f1 EAU mice also
developed more severe retinal angiogenesis. Inflammation in the LysM-Cre-SOCS3f11f1 EAU
mice was characterised by enhanced neutrophil infiltration and greatly increased cytokine
expressions. In addition, the bone marrow-derived macrophages from LysM-Cre-SOCS3f11fl
mice expressed M2 makers and produced more IL-10 and VEGF-A compared to the cells
from wr mice. Finally, we found that blocking CCL2 or VEGF-A alone was not sufficient to
suppress chronic inflammation-mediated retinal angiogenesis. However, systemic inhibition
of arginase-1 activity was effective in reducing chronic EAU induced retinal angiogenesis.
Thus, arginase inhibition could be a novel therapeutic strategy to control retinal
neovascularisation related to long-standing uveoretinitis.